Stimulation system and method for treating fragile bone disorders

ABSTRACT

According to one aspect, a stimulation system is provided for electrically stimulating a predetermined site to treat a fragile bone disorder or condition. The system includes an electrical stimulation lead adapted for implantation into a subcutaneous area in communication with a predetermined site, wherein the site is neuronal tissue that is associated with C2/C3 dermatome area. The stimulation lead includes one or more stimulation electrodes adapted to be positioned in the predetermined site. The system also includes a stimulation source that generates the stimulation pulses for transmission to the one or more stimulation electrodes of the stimulation lead to deliver the stimulation pulses to the predetermined site to treat a fragile bone disorder or condition.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/109,819, filed Apr. 25, 2008, now U.S. Pat. No. 8,244,361, whichclaims the benefit of U.S. Provisional Application No. 60/914,200, filedApr. 26, 2007 and U.S. Provisional Application No. 60/938,600, filed May17, 2007, the disclosures of which are fully incorporated herein byreference.

BACKGROUND

This application relates to neuronal tissue stimulation for treatingfragile bone disorders, such as osteoporosis, and more particularly tomodulating neuronal tissue in the C2/C3 dermatome area, or stimulatingcervical nerve roots and/or stimulating cranial nerves.

Osteoporosis is a systemic skeletal disease, characterized by low bonemass and deterioration of bone tissue, with a consequent increase inbone fragility and susceptibility to fracture. In the U.S., thecondition affects more than 25 million people and causes more than 1.3million fractures each year, including 500,000 spine, 250,000 hip and240,000 wrist fractures annually. Hip fractures are the most seriousconsequence of osteoporosis, with 5-20% of patients dying within oneyear, and over 50% of survivors being incapacitated.

The elderly are at greatest risk of osteoporosis, and the problem istherefore predicted to increase significantly with the aging of thepopulation. Worldwide fracture incidence is forecasted to increasethree-fold over the next 60 years, and one study estimated that therewill be 4.5 million hip fractures worldwide in 2050.

Women are at greater risk of osteoporosis than men. Women experience asharp acceleration of bone loss during the five years followingmenopause. Other factors that increase the risk include smoking, alcoholabuse, a sedentary lifestyle and low calcium intake.

There are currently two main types of pharmaceutical therapy for thetreatment of osteoporosis. The first is the use of anti-resorptivecompounds to reduce the resorption of bone tissue. Estrogen is anexample of an anti-resorptive agent. It is known that estrogen reducesfractures. In addition, Black, et al. in EP 0605193A1 report thatestrogen, particularly when taken orally, lowers plasma levels of lowdensity lipoproteins (LDL's) and raises those of the beneficial highdensity lipoproteins (HDL's). However, estrogen failed to restore boneback to young adult levels in the established osteoporotic skeleton.Furthermore, long-term estrogen therapy, however, has been implicated ina variety of disorders, including an increase in the risk of uterinecancer, endometrial cancer and possibly breast cancer, causing manywomen to avoid this treatment. The significant undesirable effectsassociated with estrogen therapy support the need to develop alternativetherapies for osteoporosis that have the desirable effect on serum LDLbut do not cause undesirable effects.

A second type of pharmaceutical therapy for the treatment ofosteoporosis is the use of anabolic agents to promote bone formation andincrease bone mass. This class of agents is expected to restore bone tothe established osteoporotic skeleton. Such agents can includeprostaglandin agonists as described in U.S. Pat. No. 4,112,236, GB1,478,281, GB1479156, U.S. Pat. Nos. 4,175,203, 4,055,596, 4,175,203,3,987,091 and 3,991,106.

Recently, a link between the sympathetic nervous system and the skeletalsystem has been established. For example, increases in sympathetic tonemediates bone loss through suppression of bone formation by enhancementof osteoclast activity and reduction in osteoblast activity (Kondo etal., J Biol Chem. 2005 Aug. 26; 280(34):30192-200). Yirmirya et al.,have recently shown that major depression results in an increase in bonenorepinephrine levels resulting in increases in bone loss (Yirmiya etal., Proc Natl Acad Sci USA. 2006 Nov. 7; 103:16876-81).

Although there are a variety of osteoporosis therapies there is acontinuing need and a continuing search in this field of art foralternative osteoporosis therapies. In addition, there is a need forbone fracture healing therapies. The present inventor is the first toutilize neurostimulation of the peripheral nervous system to treat boneloss or fragile bone disorders/diseases, such as osteoporosis.

SUMMARY

The present application is designed for the treatment of any type offragile bone condition or any disorder relating to bone loss includingbut not limited to osteoporosis, age-associated osteoporosis,postmenopausal osteoporosis, osteitis deformans (Paget's disease),osteogenesis imperfecta (brittle bones), and osteopetrosis,osteoarthrosis/osteoarthritis. The degeneration of joints orosteoarthrosis as it is called in Europe or osteoarthritis as it iscalled in the USA, are also included.

According to one aspect, a neurological stimulation system is providedfor electrically stimulating a predetermined site, for example acervical dermatome area (e.g., C2 dermatome area/C3 dermatome area),cervical nerve roots and/or cranial nerves to treat one or more fragilebone disorders, such as osteoporosis. The system includes an electricalstimulation lead adapted for implantation into a subcutaneous area incommunication with the predetermined site for electrical stimulation ofthe predetermined site, more particularly the C2/C3 dermatome area. Thestimulation lead includes one or more stimulation electrodes adapted tobe positioned in the subcutaneous area of the predetermined site todeliver electrical stimulation pulses to the predetermined site. Thesystem also includes a stimulation source that generates the electricalstimulation pulses for transmission to the one or more stimulationelectrodes of the stimulation lead. The stimulation of the site, forexample the C2/C3 dermatome, can result in decreases in norepinephrineand other catecholamine concentrations, increases in osteoblastactivity, and/or decreases in osteoclast activity thereby reducing,abrogating or treating fragile bone disorders. Yet further, the systemincludes a means for programming the stimulation source, for example ahand-held programmer can be used to externally program the stimulationsource.

The foregoing has outlined rather broadly certain features and/ortechnical advantages in order that the detailed description that followsmay be better understood. Additional features and/or advantages will bedescribed hereinafter which form the subject of the claims. It should beappreciated by those skilled in the art that the conception and specificembodiment disclosed may be readily utilized as a basis for modifying ordesigning other structures for carrying out the same purposes. It shouldalso be realized by those skilled in the art that such equivalentconstructions do not depart from the spirit and scope of the appendedclaims. The novel features, both as to organization and method ofoperation, together with further objects and advantages will be betterunderstood from the following description when considered in connectionwith the accompanying figures. It is to be expressly understood,however, that each of the figures is provided for the purpose ofillustration and description only and is not intended as a definition ofthe limits of the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

For a more complete understanding of the present application, referenceis now made to the following descriptions taken in conjunction with theaccompanying drawing, in which:

FIG. 1 illustrates an example neurological stimulation system forelectrically stimulating peripheral nerves or neuronal tissue to treatone or more fragile bone disorders or conditions;

FIGS. 2A-2I illustrate example electrical stimulation leads that may beused to electrically stimulate the peripheral nerves or neuronal tissueto treat one or more fragile disorders or conditions;

FIGS. 3A-3B illustrate examples of the human dermatome areas, includingthe cervical dermatomes, including C2 and C3 dermatome.

FIG. 4 is a block diagram of steps according to a method for treatingfragile bone disorders using a stimulation system.

DETAILED DESCRIPTION

I. Definitions

Unless defined otherwise, technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art. For purposes of the present application, the following termsare defined below.

As used herein, the use of the word “a” or “an” when used in conjunctionwith the term “comprising” in the claims and/or the specification maymean “one,” but it is also consistent with the meaning of “one or more,”“at least one,” and “one or more than one.” Still further, the terms“having,” “including,” “containing” and “comprising” are interchangeableand one of skill in the art is cognizant that these terms are open endedterms.

The term “bone remodeling” as used herein refers to the process ofrenewing the skeleton and maintaining the strength of bone. This processoccurs throughout the lifetime of the subject. Two reactions areinvolved in the process of bone remodeling, bone loss or resorption andbone growth or accretion. This remodeling occurs in a series of discretepockets of activity in the bone. These pockets are lined with twodifferent cell types called “osteoclasts” and “osteoblasts”. Osteoclasts(bone disolving or resorbing cells) are responsible for the resorptionof a portion of bone within the bone matrix, during the resorptionprocess. After resorption, the osteoclasts are followed by theappearance of osteoblasts (bone forming cells), which then refill theresorbed portion with new bone.

The term “fragile bone condition” or “fragile bone disease” as usedherein refers to a condition or disease characterized by low bone massor structural deterioration of bone tissue, leading to bone fragilityand increased susceptibility to fractures.

The term “type I osteoporosis” or “postmenopausal osteoporosis” as usedherein is usually found in women after the beginning of menopause. Theincidence in women is six to eight times higher than that in men. It hasbeen postulated that the cause of this osteoporosis is accelerated boneresorption. The increased bone turnover results in a secondary decreasein parathyroid hormone (PTH) secretion as well as a secondary reductionin the renal production of calcitriol. Patients present with trabecularbone loss with vertebral fractures or distal forearm fractures.

The term “type II osteoporosis” or “age-associated osteoporosis” or“senile osteoporosis” occurs in men or women over the age of 70. Themechanisms of this bone mass loss are thought to be increased PTHsecretion resulting from decreased gastrointestinal calcium absorptionand decreased osteoblast function. Patients usually present withfractures of the hip or vertebrae, sites that contain cortical andtrabecular bone, although fractures of the pelvis, ribs, and tibia canalso occur.

The term “osteoporosis” as used herein is defined as a general term fordescribing any disease process that results in reduction in the mass ofbone.

As used herein, the term “in communication” refers to the stimulationlead being adjacent, in close proximity, in contact, or directly next toor directly on the predetermined stimulation site. Thus, one of skill inthe art understands that the lead is “in communication” with thepredetermined site if the stimulation results in a modulation ofneuronal activity.

As used herein, the term “dermatome” refers to the area of skininnervated by a single dorsal root. One of skill in the art realizesthat the boundaries of dermatomes are not distinct and in fact overlapbecause of overlapping innervations by adjacent dorsal roots. Dermatomesare divided into sacral (S), lumbar (L), thoracic (T) and cervical (C).Yet further, as used herein, the term “dermatome” includes all theneuronal tissues located within the region or adjacent to the dermatomearea, for example, it may include any peripheral nerve, for example, anycervical nerve root (e.g., C1, C2, C3, C4, C5, C6, C7 and C8) that mayinnervate the dermatome. For example, the C2/C3 dermatome area maycomprise any peripheral nerve (e.g., the occipital nerve (the greater,the lesser, the third and the suboccipital nerve), the great auricularnerve, the transverse cervical nerve, the supraclavicular nerve, spinalaccessory nerve, phrenic nerve, dorsal scapular nerve) that arises fromthe C2 or C3 nerve root.

As used herein the term “modulate” refers to the ability to regulatepositively or negatively neuronal activity. Thus, the term modulate canbe used to refer to an increase, decrease, masking, altering, overridingor restoring neuronal activity. Modulation of neuronal activity affectsfragile bone disorders or conditions of a subject.

As used herein, the term “neuronal” refers to a neuron which is amorphologic and functional unit of the brain, spinal column, andperipheral nerves.

As used herein, the term “nervous system” comprises two components, thecentral nervous system, which is composed of the brain and the spinalcord, and the peripheral nervous system, which is composed of gangliaand the peripheral nerves that lie outside the brain and the spinalcord. One of skill in the art realizes that the nervous system may beseparated anatomically, but functionally they are interconnected andinteractive.

As used herein, the term “peripheral nervous system” comprises severalparts, for example the autonomic system (parasympathetic andsympathetic), the somatic system and the enteric system.

As used herein, the term “stimulate” or “stimulation” refers toelectrical and/or magnetic stimulation that modulates the predeterminedsites in the brain.

As used herein, the term “treating” and “treatment” refers to modulatingcertain areas of the brain so that the subject has an improvement in thedisease, for example, beneficial or desired clinical results. Forpurposes of this application, beneficial or desired clinical resultsinclude, but are not limited to, alleviation of symptoms, diminishmentof extent of disease, stabilized (i.e., not worsening) state of disease,delay or slowing of disease progression, amelioration or palliation ofthe disease state, and remission (whether partial or total), whetherdetectable or undetectable. One of skill in the art realizes that atreatment may improve the disease condition, but may not be a completecure for the disease.

II. Differential Activation of the Sympathetic and ParasympatheticNervous System by C2/C3 Dermatome Electrical Stimulation at VariousFrequencies.

Introduction

Bone loss disorders arise from an imbalance in the formation of newhealthy bone and the resorption of old bone, skewed toward a net loss ofbone tissue. Recently, connections between autonomic nervous systemactivity and bone growth and loss have been discovered (Kondo et al.,2005; Yirmiya et al., 2006). The inventor applied electrical stimulationto the C2/C3 dermatome at various frequencies and measured changes insympathetic and parasympathetic autonomic nervous system activity.

Methods

Volunteers were given electrical stimulation at frequencies ranging from0 to 300 Hz. Adrenaline (epinephrine), noradrenaline (norepinephrine),dopamine and prolactin levels were measured from blood samples after 1hour of stimulation. Electrocardiograms were recorded and spectralanalysis of heart rate variability over 1 hour provided the normalizedmarkers of cardiac sympathetic (LF_(nu)) and vagal (HF_(nu)) modulationof the sinoatrial node activity and of the sympathovagal balance(LF/HF).

Results

Stimulation at frequencies of 6 Hz and 12 Hz produced a netparasympathetic activation, whereas stimulation at frequencies of 10 Hzand above 18 Hz resulted in greater activation of the sympatheticresponse.

TABLE 1 shows the levels of adrenaline, noradrenaline, dopamine andprolactin in the bloodstream in response to burst or tonic stimulationof the indicated frequencies between 0 and 40 Hz. As an example in onevolunteer stimulation frequencies of 10, 18, 20, and 40 Hz resulted in arobust increase in serum adrenaline levels, whereas stimulationfrequencies of 6 and 12 Hz did not. The stimulation frequencies thatactivate the sympathetic and parasympathetic system might be personspecific, but can be determined individually by heart rate variabilityrecordings and measuring adrenaline/noradrenaline blood levels.

TABLE 1 40 Patient 0 Hz 6 Hz 10 Hz 12 Hz 18 Hz 20 Hz Hz Adrenalin Level(nM) after Burst ANS Stimulation at Different Frequencies MP 117 55 6270 33 70 39 DDR 43 57 142 31 39 57 317 21/5/06 DDR 9 23 17 32 90 929/5/06 EVDV 96 87 58 19 50 18 65 Average 66.3 55.5 69.8 40.0 38.5 58.8107.5 Adrenalin Level (nM) after Tonic ANS Stimulation at DifferentFrequencies MP 94 62 62 31 56 55 55 DDR 55 47 18 80 89 23 19 15/5/06 DDR39 41 128 80 58 41 26/4/06 EVDV 136 100 Average 62.7 50.0 69.3 55.5 67.739.7 37.0 NorAdrenalin Level (nM) after Burst ANS Stimulation atDifferent Frequencies MP 1132 607 657 686 857 953 654 DDR 347 552 429371 337 368 EVDV 405 405 405 330 347 398 438 Average 628 521.3 497.0462.3 513.7 573.0 546.0 NorAdrenalin Level (nM) after Tonic ANSStimulation at Different Frequencies TM 357 501 411 342 483 426 538 DDR478 480 369 414 352 295 236 15/5/06 DDR 247 98 152 159 139 117 26/4/06MP 568 500 Average 412.5 394.8 310.7 305.0 324.7 279.3 387.0 DopamineLevel (nM) after Burst ANS Stimulation at Different Frequencies MP 32 6535 37 70 37 77 DDR 64 53 36 53 21/5/06 DDR 122 59 162 34 32 69 3629/5/06 EVDV 25 45 58 25 25 Average 72.7 62.0 68.8 38.7 49.0 46.0 46.0Dopamine Level (nM) after Tonic ANS Stimulation at Different FrequenciesMP 29 22 TM 67 65 135 70 94 120 120 DDR 56 59 46 116 108 26/4/06 DDR 191128 75 104 31 32 26 15/5/06 Average 85.8 68.5 85.3 96.7 77.7 76.0 73.0Prolactin Level (nM) after Burst ANS Stimulation at DifferentFrequencies MP 148 135 138 122 116 123 147 EVDV 117 79 65 63 58 57 69DDR 209 177 205 209 154 151 195 29/5/06 DDR 132 196 182 231 267 198 19521/5/06 Average 151.5 146.75 147.5 156.25 148.75 132.25 151.5 ProlactinLevel (nM) after Tonic ANS Stimulation at Different Frequencies TM 217284 190 193 198 247 236 DDR 175 153 150 205 178 276 26/4/06 DDR 186 264186 231 125 143 160 15/5/06 MP 153 116 98 106 101 113 Average 182.75204.25 156 183.75 150.5 222 169.7

TABLE 2 shows the HRV Ratio in response to stimulation at frequenciesbetween 0 and 40 Hz. Stimulation frequencies of 0, 10, 18, 20, and 40 Hzresulted in a net increase in the HRV Ratio, whereas stimulationfrequencies of 6 and 12 Hz resulted in a net decrease in the HRV Ratioin this person. For other people the frequencies required for activatingthe parasympathetic and sympathetic system respectively might bedifferent.

TABLE 2 HRV Ratio (LF/HF) after ANS Stimulation at Different FrequenciesPatient 0 Hz 6 Hz 10 Hz 12 Hz 18 Hz 20 Hz 40 Hz 1 1.906 0.737 1.306 0.651.524 1.735 2 0.758 0.856 1.4 3.37 Average 1.332 0.7965 1.353 0.65 3.371.524 1.735

Discussion

Increased levels of adrenaline in the bloodstream and an increase inLF/HF were both indications of increased sympathetic activity.Conversely, stable adrenaline levels and a decreased LF/HF wereindications of increased parasympathetic activity. The inventor foundthat specific frequencies of autonomic nervous system (ANS) stimulationwere capable of eliciting one of these two opposing autonomic responses.Since it has been demonstrated that autonomic balance directly affectsthe balance between bone growth and bone loss, it is envisaged thatspecific frequencies of autonomic nervous system stimulation can beapplied to promote bone growth and/or inhibit bone loss.

III. Detailed Discussion of the Procedure

The present method acts to stimulate nerve afferents which in turnstimulate the brain and cause/allow the brain to act in the bestinterest of the host through use of the brain's natural mechanisms. Itmay come as a surprise to one skilled in the art to learn thatstimulation of nervous tissue or at least one of a patient's nerveslocated in or associated with the C2/C3 dermatome area may be used totreat the maladies disclosed herein. While the normal functions of thenerves associated with the C2/C3 dermatome area would not suggest to oneskilled in the art that they could be used to treat, for example,fragile bone disorders, the nerves associated with the C2/C3 dermatomearea have qualities which make them suited for the contemplated methodsof treatment. For example, an increase in sympathetic tone can mediatedeleterious effects on the skeletal system altering bone remodeling andskewing it towards bone resorption thereby increasing the fragility ofthe skeletal system resulting in fragile bone disorders. Thus, theneurostimulation system can be used to modulate or decrease thesympathetic nervous system by decreasing bone norepinephrine levels orother catecholamines, increasing osteoblast activity, and/or decreasingosteoclast activity.

This section will describe some exemplary details and considerations tobe taken into account during the procedure, as further described by FIG.4. FIGS. 1A-1B illustrate example neurological stimulation systems 10for stimulating a predetermined area to treat one or more fragile boneconditions. In general terms, stimulation system 10 includes animplantable pulse generating source or stimulation source 12 and one ormore implantable electrodes or stimulation leads 14, as illustrated inFIGS. 2A-2I for applying stimulation pulses to the predetermined site,as discussed below.

Implant Stimulation Lead (100)

FIGS. 3A-3B illustrate the typical location of the various dermatomes inthe human body. The predetermined site may be selected from the groupconsisting of C2/C3 dermatome area (comprising peripheral nerves such asthe occipital nerve (the greater and lesser occipital nerve, lesseroccipital nerve, great auricular nerve, third occipital nerve,transverse cervical nerve, supraclavicular nerves, spinal accessorynerve, phrenic nerve, dorsal scapular nerve), cervical nerve roots(e.g., C1, C2, C3, C4, C5, C6, C7 and C8) and/or cranial nerves (e.g.,olfactory nerve, optic, nerve, oculomoter nerve, trochlear nerve,trigeminal nerve, abducent nerve, facial nerve, vestibulocochlear nerve,glossopharyngeal nerve, vagal nerve, accessory nerve, and hypoglossalnerve).

In one exemplary embodiment, the predetermined site is the C2/C3dermatome area that comprises the cervical nerve roots (C2, C3) and anyperipheral nerve that derives or arises from the C2 or C3 cervical nerveroots associated (e.g., the occipital nerve (the greater, the lesser,the third and the suboccipital nerve), the great auricular nerve, thetransverse cervical nerve, the supraclavicular nerve, spinal accessorynerve, phrenic nerve, dorsal scapular nerve). In certain embodiments oneor more stimulation electrodes 18 are positioned in the C2/C3 dermatomearea, subcutaneously, about midline just below the inion or externaloccipital proturberance.

FIGS. 2A-2I illustrate example stimulation leads 14 that may be used forelectrically stimulating the predetermined site to treat one or morefragile bone disorders. As described above, each of the one or morestimulation leads 14 incorporated in stimulation system 10 includes oneor more stimulation electrodes 18 adapted to be positioned incommunication with the predetermined site and used to deliver to thestimulation pulses received from stimulation source 12. For the purposesdescribed herein, and as those skilled in the art will recognize, whenan embedded stimulation system, such as the Bion®, is used, it ispositioned similar to positioning the lead 14. Techniques for implantingstimulation leads such as stimulation lead 14 are known to those skilledin the art.

A percutaneous stimulation lead 14, such as example stimulation leads 14a-d, includes one or more circumferential electrodes 18 spaced apartfrom one another along the length of stimulating portion 20 ofstimulation lead 14. Circumferential electrodes 18 emit electricalstimulation energy generally radially (i.e., generally perpendicular tothe axis of stimulation lead 14) in all directions.

A laminotomy, paddle, or surgical stimulation lead 14, such as examplestimulation leads 14 e-i, includes one or more directional stimulationelectrodes 18 spaced apart from one another along one surface ofstimulation lead 14. Directional stimulation electrodes 18 emitelectrical stimulation energy in a direction generally perpendicular tothe surface of stimulation lead 14 on which they are located.

Although various types of stimulation leads 14 are shown as examples,stimulation system 10 may comprise any suitable type of stimulation lead14 in any suitable number. In addition, stimulation leads 14 may be usedalone or in combination. For example, medial or unilateral stimulationof the predetermined site may be accomplished using a single electricalstimulation lead 14 implanted in communication with the predeterminedsite in one side of the head, while bilateral electrical stimulation ofthe predetermined site may be accomplished using two stimulation leads14 implanted in communication with the predetermined site in oppositesides of the head.

In addition to electrical stimulation, other forms of stimulation can beused, for example magnetic. Magnetic stimulation can be provided byinternally implanted probes or by externally applied directed magneticfields, for example, U.S. Pat. Nos. 6,592,509; 6,132,361; 5,752,911; and6,425,852, each of which is incorporated herein in its entirety. Quickpulses of magnetic stimulation can be applied externally ortranscranially, for example repetitive transcranially magneticstimulation (rTMS).

In another embodiment, the stimulation is percutaneous. In“percutaneous” electrical nerve stimulation (PENS), needles are insertedto an appropriate depth around or immediately adjacent to apredetermined stimulation site, and then stimulated.

Couple Stimulation Source to Stimulation Lead (102)

In certain embodiments, stimulation source 12 is coupled directly to aconnecting portion 16 of stimulation lead 14. In certain otherembodiments, stimulation source 12 is incorporated into the stimulationlead 14 and stimulation source 12 instead is embedded within stimulationlead 14. For example, such a stimulation system 10 may be a Bion®stimulation system manufactured by Advanced Bionics Corporation.

In one embodiment, as shown in FIG. 1, stimulation system 10 comprisesimplantable pulse generator (IPG) 12, stimulation lead 14, controller26, and RF transmitter 24. IPG 12 typically comprises a metallic housingthat encloses the pulse generating circuitry, control circuitry,communication circuitry, battery, recharging circuitry, etc. of thedevice. An example commercially available IPG is the EON® IPG availablefrom Advanced Neuromodulation Systems, Inc. IPG 12 also typicallycomprises a header structure for electrically and mechanically couplingto stimulation lead 14. The electrical pulses generated by IPG 12 areconducted through conductors (not shown) embedded within stimulationlead 14 and delivered to tissue of the patient using electrodes 18 atdistal end 20 of stimulation lead 14. Furthermore, IPG 12 may be adaptedto communicate with external devices, such as controller 26, afterimplantation within a patient. For example, controller 26 may utilize RFtransmitter 22 to conduct wireless communications 24 with IPG 12 afterIPG 12 is implanted within a patient.

In one embodiment, the stimulation source transcutaneously stimulatestarget neural tissue. In “transcutaneous” electrical nerve stimulation(TENS), a stimulation source and one or more patch electrodes aredisposed external to the patient. The stimulation source may be worn inan appropriate fanny pack or belt. The patch electrode is typicallyapplied on the skin immediately above the appropriate neural tissue. Thestimulation source delivers electrical stimulation to the patchelectrode thereby stimulating the adjacent neural tissue.

Generate and Transmit Trial Stimulation Pulses (104)

Stimulation source 12 controls the stimulation pulses transmitted to oneor more stimulation electrodes 18 located on a stimulating portion 20 ofstimulation lead 14, positioned in communication with a predeterminedsite to stimulate peripheral nerves, according to suitable stimulationparameters (e.g., duration, amplitude or intensity, frequency, pulsewidth, etc.). At step 104, stimulation source 12 is activated togenerate and transmit stimulation pulses via one or more stimulationelectrodes 18. A doctor, the patient, or another user of stimulationsource 12 may directly or indirectly input stimulation parameters forcontrolling the nature of the stimulation provided.

It is envisaged that the patient will require intermittent assessmentwith regard to patterns of stimulation. Different electrodes on the leadcan be selected by suitable programming, such as that described in U.S.Pat. No. 5,938,690, which is incorporated by reference here in full.Utilizing such a program allows an optimal stimulation pattern to beobtained at minimal voltages. This ensures a longer battery life for theimplanted systems.

In some embodiments, a doctor, the patient, or another user ofstimulation source 12 may use a controller 26 located external to theperson's body to provide control signals for operation of stimulationsource 12. Controller 26 provides the control signals to wirelesstransmitter 22, wireless transmitter 22 transmits the control signalsand power to the wireless receiver of stimulation source 12, andstimulation source 12 uses the control signals to vary the stimulationparameters of stimulation pulses transmitted through stimulation lead 14to the predetermined site. Thus, the external controller 26 can be forexample, a handheld programmer, to provide a means for programming theIPG. Also, external controller 26 and transmitter 22 can be integratedin a single device.

Assess Stimulation Efficacy (106)

At step 106, a doctor may conduct tests or analyses for example todetermine bone mass, to determine norepinephrine levels, and/or todetermine osteoblast/osteoclast activity. Fragile bone disorders can bemonitored by measuring bone mineral density (BMD) using standardtechniques, for example dual-energy x-ray absorptiometry (DEXA), andquantitative computed tomography (QCT). Peripheral bone density testingcan also be used.

Modify Protocol and Repeat Trial Stimulations (108)

If the one or more fragile bone disorders and/or conditions are notsufficiently improved, one or more stimulation parameters may beadjusted, stimulation lead 14 may be moved incrementally or evenre-implanted, or both of these modifications may be made at step 108 andthe trial stimulation and analysis repeated until the one or morefragile bone disorders and/or conditions are sufficiently improved. Oncethe stimulation parameters have been properly set and stimulation lead14 has been properly positioned such that the one or more conditions aresufficiently improved, intra-implantation trial stimulation is complete.

In some embodiments, it is considered that several cycles ofintra-implantation trials may be required. In preferred embodiments, acomparison of the treatment efficacy between multiple cycles ofintra-implantation trial stimulation will be used to determine theoptimal location and stimulation protocol. In further embodiments, steps104 through 108 represent a repetitive cycle that ends when an optimallocation and protocol have been selected. In some embodiments, once thestimulation lead 14 has been properly positioned such that boneresorption is reduced and/or bone growth is increased,intra-implantation trial stimulation may be considered complete. Inother embodiments, the intra-implantation trial stimulation is notperformed, and the method proceeds from process 102 to 110. It iscontemplated that stimulation parameters may be modified to maximize theeffectiveness of the therapy both prior to and subsequent to the end ofthe intra-implantation trial stimulations.

Parameters relating to fragile bone disorders can be measured todetermine improvement or efficacy of the treatment. Such the parameterscan include increase in bone density, increase in bone strength,induction of healthy bone growth, decrease in bone fractures and/orbreaks, modulation of calcium levels, and modulation of mineralaccumulation in the skeleton, decrease in bone norepinephrine levels,decrease in osteoclast activity, increase osteoblast in levels, increasein T-scores of at least -1 or above, increase in Z-scores. Theimprovement is any observable or measurable improvement. Thus, one ofskill in the art realizes that a treatment may improve the patientcondition, but may not be a complete cure of the disease.

Implant Stimulation Source (110)

Once stimulation lead 14 has been properly implanted and secured, andany trial stimulation completed, if necessary, stimulation source 12 isimplanted at step 110. Techniques for implanting stimulation sourcessuch as stimulation source 12 are known to those skilled in the art. Fornon-embedded systems, the implant site is typically a subcutaneouspocket formed to receive and house stimulation source 12. The implantsite is usually located some distance away from the insertion site, suchas in or near the upper chest or buttocks.

Tunnel Connection Between Stimulation Lead and Stimulation Source (112)

Where stimulation lead 14 includes connecting portion 16, connectingportion 16 may be tunneled, at least in part, subcutaneously to theimplant site of stimulation source 12 at step 112.

Input Stimulation Parameters (114)

At step 114, a doctor, the patient, or another user of stimulationsource 12 may directly or indirectly input stimulation parameters forcontrolling the nature of the electrical stimulation provided to theC2/C3 dermatome area, if not already set during any intra-implantationtrial stimulation period. Where appropriate, post-implantation trialstimulation may be conducted, over one or more weeks or months forexample, and any necessary modifications made accordingly.

Stimulation parameters can include pulse width of about 1 to about 1000microseconds, more preferable, about 50 to about 500 microseconds;frequency of about 3 to about 40 Hz, more preferably, about 3 to about20 Hz, more preferably, 6 to about 12 Hz; and amplitude of about 1 toabout 100 mA, more preferably about 1 to about 30 mA. It is known in theart that the range for the stimulation parameters may be greater orsmaller depending on the particular patient needs and can be determinedby the physician. Other parameters that can be considered may includethe type of stimulation for example, but not limited to acutestimulation, subacute stimulation, and/or chronic stimulation.

In another embodiment, a neuromodulation device can be implemented toapply burst stimulation parameters. Examples of burst stimulation arefound in U.S. Published Application No. US20060095088, and incorporatedherein by reference in its entirety. The burst stimulation may generatebursts of a plurality of electrical pulses with an inter-burst frequencyin the range of about 1 Hz to about 100 Hz, more particular, in therange of about 1 Hz to about 50 Hz. The inter-burst interval has aduration in the range of about 1 milliseconds to about 5 seconds, morepreferably, about 10 milliseconds to about 300 milliseconds. Theinter-burst interval need not be constant and can be varied in aprogrammable manner or varied pseudo-randomly by the pulse generator(e.g., random or irregular harmonics).

The patient can be in control of the stimulation parameters and/orprograms to maintain effectiveness of the stimulation system. Forexample, the patient can change the programs on a periodic basis, forexample weekly to maintain effectiveness. Other patients may increasethe stimulation during the day and decrease the stimulation parametersduring the evening or vice versa.

Thus, it may be desirable for the patient to control the therapy tooptimize the operating parameters to achieve the desired result ofdecreased bone loss or management of bone loss or treatment of fragilebone disorders or management of bone growth. For example, the patientcan alter the pulse frequency, pulse amplitude and pulse width using ahand held radio frequency device that communicates with the IPG. Oncethe operating parameters have been altered by the patient, theparameters can be stored in a memory device to be retrieved by eitherthe patient or the clinician. Yet further, particular parameter settingsand changes therein may be correlated with particular times and days toform a patient therapy profile that can be stored in a memory device.

Following post-implantation, the efficacy of the system can bedetermined by utilizing any of the well known and described methods toassess various or evaluate improvements of symptoms associated with afragile bone disease and/or disorder. Exemplary methods are describedabove under step 106 and incorporated herein by reference.

Although example steps are illustrated and described, the presentapplication contemplates two or more steps taking place substantiallysimultaneously or in a different order. In addition, the presentapplication contemplates using methods with additional steps, fewersteps, or different steps, so long as the steps remain appropriate forimplanting stimulation system 10 into a person for stimulation of the apredetermined site, such as C2/C3 dermatome area to treat one or morefragile bone disorders or conditions.

IV. Types of Fragile Bone Conditions, Disorders, or Diseases

Osteoporosis is common in the elderly of both sexes but is morepronounced in postmenopausal women. Osteoporosis may occur as a primarydisorder or as a secondary complication of several diseases. It isproposed that genetic factors determine the size of the bone massachieved in young adulthood. With aging, the increased osteoclasticfunction and the slowing of osteoblastic activity induced by endocrineinfluences, particularly decreased estrogen levels, result in a netnegative balance in the continued turnover of bone. Osteoporosis causesbone pain owing to microfractures; results in loss in height andstability of the vertebral column; and predisposes to fractures offemoral necks, wrists, and vertebrae. The condition remains asymptomaticuntil skeletal fragility is well advanced.

Paget's disease is currently considered to be a slow paramyxoviralinfection of osteoblasts and then osteoclasts. The condition is dividedinto an initial osteolytic stage, followed by a mixedosteolytic-osteoblastic stage, evolving ultimately into burn-outquiescent osteosclerotic stage. Because new bone formation in activedisease is disordered and poorly mineralized, it is soft and porous,lacks structural stability, and is vulnerable to fracture or deformationunder stress. Patients may demonstrate fractures, nerve compression,osteoarthritis, and skeletal deformities.

Osteogenesis imperfecta or brittle bones refers to a group of closelyrelated genetic disorders caused by qualitative or quantitative abnormalsynthesis of type I collagen, constituting about 90% of the matrix ofbone. Syndromes range from one variant (type II) that is uniformly fatalin the perinatal period (from multiple bone fractures) to other variantsmarked by increased predisposition to fracture but compatible withsurvival. Morphologically the basic change in all is osteopenia or toolittle bone, with marked thinning of the cortices and rarefication ofthe trabeculae.

Osteopetrosis refers to a group of rare hereditary diseasescharacterized by overgrowth and sclerosis of bone, with markedthickening of the cortex and narrowing or filling of the medullarycavity impairing hematopoiesis. Despite too much bone, it is brittle andfractures easily. The autosomal recessive form is evident from birth,with anemia, neutropenia, infections and eventual death. The autosomaldominant form is benign but predisposes to fractures. Common to allforms is a hereditary defect in osteoclast function resulting in reducedbone resorption and enhanced net bone overgrowth.

Fragile bone disorders can be diagnosed and/or monitored by measuringbone mineral density (BMD) using standard techniques, for exampledual-energy x-ray absorptiometry (DEXA), and quantitative computedtomography (QCT). Peripheral bone density testing can also be used. BMDmeasurement is given as a T-score and a Z-score. The T score comparesthe patients's bone density with the average bone density of 25- to30-year-olds of the same sex. This age group is used because bonedensity is at its highest at this age. A T-score of at least −1 to 0 orgreater is considered normal. A T-score between −1 and −2.5 indicatessome bone loss (osteopenia) and a risk of osteoporosis. A T-score ofless than −2.5 is diagnostic of osteoporosis. The Z score compares apatient's bone density with that of people of the same age, sex, weight,and ethnic or racial origin. The Z-score can be used to classify thetype of osteoporosis. A score of at about −1.5 indicates primaryosteoporosis, which is age related. A score of less than −1.5 canindicate secondary osteoporosis, which is associated with calcitoninimbalance, malabsorption conditions (e.g., celiac disease, cysticfibrosis).

Although certain representative embodiments and advantages have beendescribed in detail, it should be understood that various changes,substitutions and alterations can be made herein without departing fromthe spirit and scope of the appended claims. Moreover, the scope of thepresent application is not intended to be limited to the particularembodiments of the process, machine, manufacture, composition of matter,means, methods and steps described in the specification. As one ofordinary skill in the art will readily appreciate when reading thepresent application, other processes, machines, manufacture,compositions of matter, means, methods, or steps, presently existing orlater to be developed that perform substantially the same function orachieve substantially the same result as the described embodiments maybe utilized. Accordingly, the appended claims are intended to includewithin their scope such processes, machines, manufacture, compositionsof matter, means, methods, or steps.

What is claimed is:
 1. A method of treating a fragile bone disorder in apatient comprising: surgically implanting a stimulation leadsubcutaneously with one or more electrodes in subcutaneous tissueunderneath skin of the patient and above an occipital region of theskull of the patient identified as having a fragile bone disorder;coupling the stimulation lead to a pulse generator; programming thepulse generator to generate stimulating pulses at a frequency that iseffective in modifying sympathetic or parasympathetic response in thesubject; operating the pulse generator according to the programming togenerate stimulation pulses for delivery to nerve fibers of theoccipital nerve using one or more electrodes of the stimulation lead totreat the fragile bone disorder, wherein the generation of stimulationpulses further includes performing heart rate variability recordings;and examining the patient to determine whether the stimulation pulsesare effective in affecting bone density in the patient.
 2. The method ofclaim 1, wherein the efficacy of the treatment increases according tothe amplitude of the stimulation pulses.
 3. The method of claim 1,wherein the fragile bone disorder is osteoporosis.
 4. The method ofclaim 1, wherein the stimulation lead is a percutaneous lead.
 5. Themethod of claim 1, wherein the stimulation lead is a laminotomy, paddle,or surgical lead.
 6. The method of claim 1, wherein the stimulation leadand the pulse generator are contained in one unit.
 7. The method ofclaim 1, wherein the stimulation decreases bone norepinephrine levels.8. The method of claim 1, wherein the stimulation decreases osteoclastactivity.
 9. The method of claim 1, wherein the stimulation increasesosteoblast activity.